Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages

Ye Hu,Xiaoqing Xu,Yong Zhao,Xin Wang,Xuetao Cao,Jia Xu,Jiacheng Wu,Chunmei Wang,Yuanyuan Ding,Yangyang Chai,Bingjing Wang,Zhongyang Shen,Jiaying Song

doi:10.1038/s41419-021-04032-9

Abstract

Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.

Highlights

IntroductionEpigenetic factors remodel chromatin architecture to facilitate or inhibit the access of the transcription factors or regulatory proteins to the promoter region of genes, including those involved in the innate immune response and inflammation [3, 4]
Chromatin remodeling plays a critical role in regulating gene transcription [1, 2]
ARID1A selectively promotes IFN-I production in antiviral immune response Arid1a expression was quite abundant in immune-related cells and of Arid1a in myeloid cells has no effect on the development of immune cells

Summary

Introduction

Epigenetic factors remodel chromatin architecture to facilitate or inhibit the access of the transcription factors or regulatory proteins to the promoter region of genes, including those involved in the innate immune response and inflammation [3, 4]. As the most studied epigenetic regulators, histone modifications such as methylation, acetylation, and ubiquitination, are precisely regulated to control the transcription of immune-associated genes [5]. Among those most important cytokines, type I interferons (IFN-I) including IFN-α and IFN-β have strong antiviral activities and play important roles in the pathogenesis of inflammatory diseases [4, 6, 7]. The crosstalk among multiple regulatory proteins and their synergistic effects in regulating transcription of Ifn-I during innate immune response remains to be fully understood

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Conclusion